Ataxia telangiectasia (A-T) is a rare childhood disorder characterized by the eventual loss of motor control, moderate to severe immunodeficiency, premature aging, and a pronounced predisposition to cancer. The gene defective in A-T has recently been identified (atm). The vast majority of mutations that produce the AT phenotype generate ATM protein truncations. A number of studies have recently shown that the aminoglycoside family of antibiotics mediate suppression of termination codons, albeit in a context-dependent fashion that can be exceedingly modest. We have examined global gene expression differences between human A-T and wild type cell lines. An unexpected outcome of these studies is the observation that ATM expression can be pharmacologically up-regulated. Consequently, it may be possible to induce ATM activity in an A-T genetic background by using drugs that suppress nonsense mutations in combination with agents that activate the atm promoter. The proposed research program seeks to (1) identify the global biochemical signals that activate the atm promoter, (2) assess the mechanism of action of atm promoter activating drugs, (3) evaluate a library of FDA-approved drugs for their ability to suppress nonsense mutations and serve as adjuvants for the aminoglycoside antibiotic family, (4) assess the combinatorial action of drugs that suppress nonsense mutations and activator atm promoter function, and (5) examine the effect of these agents on ATM induction and activation in A-T cell lines.